An intensive research effort in the field of cephalosporin antibiotics has produced a number of clinically significant cephalosporin compounds. One of the more recent developments in this area has been the discovery of cephem compounds directly substituted with halogen at the C-3 position. A number of 3-halo-3- cephems have been described by Chauvette in U.S. Pat. Nos. 3,925,372, 4,064,343 and 3,962,227. These potent antibiotic compounds are prepared by halogenation of the corresponding 3-hydroxy-3-cephems. The halogenation of 3-hydroxy-3-cephems to provide 3-chloro and 3-bromo-3-cephems has typically been carried out by reacting the 3-hydroxy-3-cephem compounds with brominating or chlorinating agents including phosgene, oxalyl chloride, thionyl chloride, thionyl bromide and phosphorus halides such as phosphorus trichloride and phosphorus tribromide, usually in the presence of dimethylformamide.
This invention is directed to a novel class of halogenating agents which are useful in preparing 3- halo-3-cephems.
More particularly this invention is directed to highly reactive halogenating compounds having the empirical formula ##STR1## wherein X is Cl or Br and Z is hydrogen, halo, C.sub.1 -C.sub.4 alkyl, or C.sub.1 -C.sub.4 alkoxy, derived from the reaction of a triaryl phosphite and chlorine or bromine respectively.
A number of halogenating agents derived from halogens and phosphorus or phosphorus containing compounds have been described. Known chlorinating and brominating compounds of this type include phosphorus trichloride, phosphorus tribromide, phosporyl chloride, phosphoryl bromide, phosphorus pentachloride, phosphorus pentabromide, triphenyl phosphite dichloride, triphenyl phosphite dibromide, triphenylphosphine dichloride, triphenylphosphine dibromide, catechyl phosphorus tribromide.
Of those prior art compounds, those most closely related to the present compounds are the triphenyl phosphite dihalides which have an empirical formula identical to that of the present compounds. See, for example, D. G. Coe, S. R. Landauer, and H. N. Rydon, J. Chem. Soc., 2281 (1954) and H. N. Rydon and B. L. Tonge, J. Chem. Soc., 3043 (1956). Although both the present triaryl phosphite-halogen compounds and the prior art triaryl phosphite dihalides have identical empirical formulas and are derived generally from the reaction of a triaryl phosphite and chlorine or bromine, physical and chemical data have unequivocally demonstrated the existence of two discrete molecular forms: a kinetic form, described and claimed herein, and a thermodynamically stable form described in the prior art. The halogenating compounds of the present invention have been shown to exhibit marked differences in both physical characteristics and in chemical reactivity when compared with triaryl phosphite dihalides described in the art. Most significantly the triaryl phosphite-halogen compounds of the present invention have been found to be far superior as halogenating agents when compared to the corresponding prior art triaryl phosphite dihalides.
The present compounds are distinguished from the triphenyl phosphite dihalides in the prior art in that the present compounds are the kinetically controlled products of the reaction of a triaryl phosphite and chlorine or bromine; the compounds described in the prior art are the thermodynamically controlled products from the same reactants. In other words the present halogentating compounds can be described as intermediates, previously unrecognized, in the preparation of the prior art triaryl phosphite dihalides from triaryl phosphites and chlorine or bromine.
The present halogenatng compounds can be employed advantageously in the preparation of known 3-halo-3-cephem antibiotic compounds.